1. Field of the Invention
This invention concerns novel derivatives of 3-(piperidin-4-yl)-1-(4′-amino-phenyl)propan-1-one as well as their use as a promnesiant drug in the treatment of neurological diseases with memory deficits. This invention has unexpectedly revealed that mixed acetylcholinesterase catalytic and peripheral inhibitors and serotonin 5-HT4 receptor agonists have promnesiant and, in particular, “anti-Alzheimer” activities.
2. Related Art
Numerous diseases and accidents can cause an amnestic syndrome:                progressive amnesia associated with dementia such as Alzheimer's Disease (AD) and vascular dementia;        cranial traumas (permanent or temporary post-traumatic amnesia);        cerebrovascular accidents;        Korsakoff syndrome;        brain tumors or injuries;        other causes linked to recurrent long-term illnesses such as epilepsy.        
AD has become the 4th cause of death in industrialized countries and there are currently no drugs on the market that appear to be capable of having a curative effect. Most of them are in fact acetylcholinesterase inhibitors (AChE) whose effectiveness is fairly poor and tolerance mediocre. It now seems necessary to associate with this symptomatic effect a curative effect by using compounds that have a plurality of actions (Multi Target Directed Ligands or MTDL).
Different MTDLs targeting AD are currently being studied. However, none of these works has yet combined in one structure an anti-AChE activity and a 5-HT4 agonist activity, even though AChE inhibitors and 5-HT4 agonists, independently of or in association with each otherii have shown promnesiant properties. Now this dual effect appears to be extremely promising in MTDL chemotherapy of AD. In fact, this approach can allow a symptomatic effect to be produced by using just one active ingredient, linked to the restoration of cholinergic transmission by the catalytic inhibitory action of AChEi, as well as a potentially curative dual effect. This is due, on the one hand, partly to the promotion of the non-amyloidogenic cleavage of the β-A protein precursor and, consequently, the formation of the neurotrophic sAPP-α, in connection with a 5-HT4 agonist effecti. On the other hand, this curative effect could also be attributable to the inhibition of a second role recently identified for AChE, that of promoting amyloid aggregation by interaction between the β-A protein and a peripheral site of the enzyme.